JPH0770056A - Cyclohexene derivative - Google Patents

Abstract

PURPOSE: To obtain a novel cyclohexene deriv. which is useful for producing a tricyclic antibacterial compd. by reacting a specific azetidinone compd. with a cyclohexenylborane deriv. in the presence of a Lewis acid.

CONSTITUTION: This cyclohexene deriv. is represented by formula I (wherein R₁ is H or a nitrogen-protective group), an example being (-)erythro-(4R)-4[(3' S)-cyclohexen-3-yl]azetidin-2-one, is obtd. by reacting an azetidinone compd. represented by formula II [wherein R₂ is 1-4C alkyl or (substd.) phenyl] with a cyclohexenylborane deriv. represented by formula III (wherein R₃ is 6-10C cycloalkyl provided the two R₃'s may combine with each other to form 1,5- cyclooctadiyl) in the presence of a Lewis acid and if necessary converting the resultant product into a compd. wherein R₁ is H, and is useful as an intermediate for producing a tricyclic antibacterial compd.

COPYRIGHT: (C)1995,JPO

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cyclohexene derivative useful for producing a compound having an antibacterial action, and a method for producing the same.

Prior Art European patent applications (EPA) 0416953A and 0422596A2 describe a new class of tricyclic antibacterial substances and methods for their preparation. The present invention relates to novel intermediates that are particularly useful for preparing compounds within this class of tricyclic antibacterial compounds.

SUMMARY OF THE INVENTION According to the invention, compounds of general formula (I):

[0004]

[Chemical 5] (Here, R ₁ represents a hydrogen atom or a nitrogen protecting group)
Will be provided.

DETAILED DESCRIPTION OF THE INVENTION The compound of formula (I) has two asymmetric centers. One is at the 4-position of the lactam ring and the other is at the 3'-position of the cyclohexene ring. Cahn, Ingold and Prelog for each chiral center
There are two possible arrangements, called R and S, based on the law of (Experientia, 1956, 12, 81). Compounds of formula (I) include (4R), (3'S) isomers and (4S),
Both (3'R) isomers, and mixtures thereof, including their racemates are included.

Examples of suitable nitrogen protecting groups R ₁ are tri (C _1-6 alkyl) silyl (eg trimethylsilyl or t-butyldimethylsilyl), C _1-4 alkylthio (eg methylthio), C _1-6 alkoxy. Methyl (eg methoxymethyl), optionally substituted benzyloxymethyl (eg benzyloxymethyl or p-methoxybenzyloxymethyl), and C _1-6 alkylsilyloxymethyl (eg t-butyldimethylsilyloxymethyl) Etc.

The nitrogen protecting group R ₁ is tri (C _1-6 alkyl)
Preference is given to silyl, such as trimethylsilyl, or especially t-butyldimethylsilyl.

Preferred as compounds of formula (I) are:
(4R), (3'S) isomer (Ia):

[0009]

[Chemical 6]

At least 50%, more preferably 70
% To 100%, for example 85% to 100%.

Preferred compounds of formula (Ia) include those in which R ₁ is hydrogen or a tri (C _1-6 alkyl) silyl group such as trimethylsilyl or especially t-butyldimethylsilyl.

The preparation of compounds of formula (I) in which R ₁ is hydrogen is carried out by the azetidinone (II):

[0013]

[Chemical 7] (Wherein R ₂ represents C _1-4 alkyl, or an optionally substituted phenyl group), and a borane derivative (II
I)

[0014]

[Chemical 8] (Wherein R ₃ each represents a C _6-10 cycloalkyl group, or two R ₃ groups together represent a 1,5-cyclooctadiyl group). When R ₃ represents a C _6-10 cycloalkyl group, this may be, for example, a monocycloalkyl group (eg cyclohexyl or 2-methylcyclohexyl) or a bicycloalkyl group (eg isopinocamphenyl).

This reaction is carried out in a solvent such as ether (eg tetrahydrofuran), hydrocarbons (eg toluene or hexane) or mixtures thereof, halogenated hydrocarbons (eg dichloromethane), halobenzenes (eg chlorobenzene), or acetonitrile. Titanium tetraisopropoxide, aluminum triisopropoxide,
It is carried out in the presence of a suitable Lewis acid catalyst such as a dialkylzinc (eg diethylzinc), a trialkylaluminum (eg triethylaluminum), or an alkylborane (eg triethylborane).

In a preferred embodiment of this method, R ₃
By using a borane derivative (III) in which is a 2-methylcyclohexyl group, or particularly an isopinocanphenyl group, (4R) represented by the general formula (Ia),
Formula (I) containing at least 70% of (3'S) isomer
The compound of Lewis acid catalysts that are particularly useful in this embodiment include titanium tetraisopropoxide and diethylzinc.

Compounds of formula (I) in which R ₁ represents a nitrogen protecting group can be prepared by introducing a nitrogen protecting group into the corresponding compound of formula (I) in which R ₁ is hydrogen by conventional methods, for example R ₁
It can be prepared by reacting with a X group (X is a leaving group such as halogen or methanesulfonate).

[0018] Thus, for example, compounds of formula (I) wherein R ₁ represents trialkylsilyl group, the corresponding compound of formula R ₁ is hydrogen (I), suitable bases include for example such as triethylamine It can be prepared by reacting with a suitable trialkylsilyl halide such as chloride in the presence of a triamine. This reaction is preferably carried out in an aprotic solvent such as N, N-dimethylformamide.

Compounds of formula (I) in which R ₁ represents an alkylthio group are prepared by reacting corresponding compounds of formula (I) in which R ₁ represents hydrogen, preferably in the presence of a base such as lithium bis (trimethylsilyl) amide. , An appropriate alkyl thiomethane sulfonate.

Azetidinone (II) is a known compound, or may be produced by a method similar to the method for producing a known compound.

Preferred azetidinones for use in the above reaction include compounds of formula (II) wherein R ₂ is methyl, or especially phenyl.

The borane derivative (III) is obtained by combining borane (R ₃ ) ₂ BH (IV) and cyclohexadiene in a solvent such as a hydrocarbon such as hexane or an ether such as tetrahydrofuran at −78 ° C. to +30.
It can be produced by reacting at a temperature in the range of ° C.

The borane compound (IV) is a known compound, or may be produced by a method similar to the known method for producing a compound. Therefore, borane (IV) in which R ₃ is a cycloalkyl group can be produced by reacting a borane dimethyl sulfide complex with a suitable cycloalkene corresponding to R ₃ . The reaction is preferably carried out in a solvent such as an ether, eg tetrahydrofuran or diethyl ether.

The preferred borane derivative (III) for use in the above reaction is cycloalkene 1S-(-)-α.
It is obtained from pinene. A more preferred borane derivative (III) for use in the above reaction is one obtained from 2-methylcyclohexene.

Compounds of formula (Ia) in which R ₁ is a nitrogen protecting group are prepared by reacting a compound of formula (V) with a ketone R ₄ COCH ₃ (where R ₄ is tri (C _1-4 alkyl) silyl). Compound:

[0026]

[Chemical 9] (Where R ₄ is tri (C _1-4 alkyl) silyl and R ₁ is a nitrogen protecting group)

Can be converted to This reaction involves treating a compound of formula (I) with a suitable base such as lithium diisopropylamide in a solvent such as tetrahydrofuran, then adding the ketone R ₄ COCH ₃ , followed by potassium t-butoxide. This can be done by adding.

The compound of the formula (V) in which R ₁ is a hydrogen atom is prepared by removing the nitrogen protecting group from the corresponding compound of the formula (V) in which R ₁ is a nitrogen protecting group by a known conventional method. Can be manufactured. Thus, for example, when R ₁ is a t-butyldimethylsilyl group, it can be selectively removed by reacting it with tetrabutylammonium fluoride and glacial acetic acid in a solvent such as tetrahydrofuran.

The compound of formula (V) in which R ₁ is a hydrogen atom can be converted into a known antibacterial substance by using the method described in EPA 0416953A2.

The novel compound represented by the formula (I), especially the (4R), (3'S) enantiomer (Ia) thereof,
The above method for preparing the compound of formula (V) from azetidinone (II) is superior to known methods because it produces the required isomer in good yield from readily available raw materials. It is advantageous.

For a fuller understanding of the invention, the following examples are given for illustrative purposes only. Infrared spectra were measured in chloroform-two solutions using an infrared Fourier transform spectrometer. Proton magnetic resonance ( ¹ H-NMR)
Was recorded at 400 MHz. Chemical shifts are reported in ppm units in descending order (d) from Me4Si used as internal standard. All temperature units are ° C. Tlc
Refers to a thin layer chromatograph on a silica plate. "Dried" refers to a solution dried over anhydrous sodium sulfate. e. e refers to the enantiomeric excess.

Example 1 Example 1 (-)-erythro- (4R) -4-[(3'S) -shik
Rohexen-3-yl] -azetidin-2-one Method A While stirring a borane dimethyl sulfide complex solution (2M tetrahydrofuran solution, 3 ml) at 0 ° under a nitrogen atmosphere, (1S)-(−)-α- Pinene (82% e
e, 12 ml) was added over 15 minutes. After stirring the mixture for 3 hours, (1S)-(-)-α-pinene (8
(2% ee, 10 ml) was added over 15 minutes, stirring was stopped immediately and left at 0 ° for 16 hours. The supernatant liquid was removed, and the precipitate was dried at -10 ° with anhydrous tetrahydrofuran (20
(ml) twice and then dried under reduced pressure. This solid was suspended in anhydrous tetrahydrofuran (30 ml) at -25 ° under a nitrogen atmosphere, 1,3-cyclohexadiene (7.5 ml) was added, and the mixture was stirred for 40 hours. To this solution was added 4-benzoyloxyazetidin-2-one (1.91 g) at -25 ° and titanium tetraisopropoxide (4.5 ml) was added to the resulting mixture. After 6 hours, titanium tetraisopropoxide (1.5
ml) was added and stirred for 16 hours. The mixture was treated with sodium citrate / citric acid (10% w / w) pH = 3 buffer (40 ml) and washed with ethyl acetate (200 m).
Extracted twice with l). The organic phase is brine (2 x 100 m
Washed with l), dried and concentrated. The obtained crude material was redissolved in n-hexane (100 ml) and extracted with acetonitrile (200 ml). The acetonitrile solution was extracted with n-hexane (3 x 50 ml) and then concentrated to obtain a yellow solid. This is subjected to flash chromatography on silica gel to give cyclohexane 7
Purified by eluting with a mixture of 0% and 30% ethyl acetate to give the title compound as a colorless solid (950 mg). HPLC: Column: Chiralpak AS 25x0.46 cm; Temperature: 2
3 °; wavelength: 220 nm; mobile phase: ethanol 70% /
n-Hexane 30%; flow rate: 0.8 ml / min; retention time: 9.9 min (area% = title compound 84.9), 2
2.4 (area% = (+)-enantiomer 15.1);
Enantiomeric excess: 69.7%

Method B (-)-erythro- (4R) -4-[(3'S) -siku
Rohexen-3-yl] -azetidin-2-one In a nitrogen atmosphere, while stirring the borane dimethyl sulfide complex solution (2M tetrahydrofuran solution, 30 ml) at 0 °, (1S)-(−)-α-pinene ( 98%
ee, 9.7 ml) was added over 15 minutes. After stirring this mixture for 3 hours, (1S)-(-)-α-pinene (98% ee, 10 ml) was added over 15 minutes, stirring was stopped immediately, and the mixture was left at 0 ° for 16 hours. The supernatant is removed and the precipitate is dried with anhydrous tetrahydrofuran (20 ml).
It was washed twice with water, cooled to -10 °, and then dried under reduced pressure. This solid was suspended in anhydrous tetrahydrofuran (30 ml) at 25 ° under a nitrogen atmosphere, and (1S)-
(−)-Α-Pinene (98% ee, 3 ml) was added. 1,3-Cyclohexadiene (9.3 ml) was added and stirred for 20 hours. To this reaction solution, a solution of 4-benzoyloxyazetidin-2-one (2.0 g) in anhydrous tetrahydrofuran (10 ml) was added at -25 °, and then diethyl zinc (1.1 M toluene solution, 4
9.1 ml) was added and the mixture was stirred at -25 ° for 5 hours. This mixture was added to sodium citrate / citric acid (10% w
/ W) pH = 3 buffer (40 ml) and extracted twice with ethyl acetate (200 ml). The organic phase was washed with brine (2x100ml), dried and concentrated. The obtained crude material was redissolved in n-hexane (100 ml) and extracted with acetonitrile (200 ml). The acetonitrile solution was extracted with n-hexane (3 x 50 ml) and concentrated to give a yellow solid containing the title compound. This was purified by flash chromatography on silica gel eluting with a mixture of 70% cyclohexane and 30% ethyl acetate to give the title compound as a colorless solid (940mg). [Α] D = -103.6 (CHCl ₃ , c = 1.06
5) HPLC: column: Chiralpak AS 25x0.46 cm; temperature: 2
3 °; wavelength: 220 nm; mobile phase: ethanol 70% /
n-Hexane 30%; flow rate: 0.8 ml / min; retention time: 9.9 min (area% = title compound 93.9), 2
2.4 (area% = (+)-enantiomer 6.1); enantiomeric excess: 87.8%

Example 2 (±) -erythro- (4RS) -4-[(3'RS)-
Cyclohexen-3-yl] -azetidin- 2-one At room temperature under nitrogen atmosphere, 1,3-cyclohexadiene (1.05 ml) was added to a borabicyclononane solution (0.5M).
Hexane solution, 20 ml) and stirred for 24 hours. Dry tetrahydrofuran (80 ml) was added, then 4-benzoyloxyazetidin-2-one (1.
A solution of 53 g) in dry tetrahydrofuran (10 ml) was added. Then, diethyl zinc (1M hexane solution,
8 ml) was added and stirred for 3 hours. Sodium citrate / citric acid pH = 3 buffer (100 ml) was added to the reaction mixture and stirred for 2 hours. The aqueous layer was extracted with ethyl acetate (200ml) and the combined organic phases were washed with saturated sodium bicarbonate (100ml) and brine (2x50ml) and dried. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (ethyl acetate content increased from 10% to 40%) to give the title compound as a colorless Isolated as an oil (485 mg). IRVmax (cm-1): 3254 (NH), 1755
(C = O-lactam) ¹ H-NMR (δ, ppm, CDCl ₃ ): 5.99
(S broad, 1H), 5.85 (m, 1H), 5.5
2 (m, 1H), 3.47 (m, 1H), 2.97 (d
dd, 1H), 2.70 (ddd, 1H), 2.32-
2.22 (m, 1H), 2.10-1.94 (m, 2
H), 1.90-1.70 (m, 2H), 1.62-
1.48 (m, 1H), 1.30-1.20 (m, 1
H)

Example 3 (±) -erythro- (4RS) -4-[(3'RS)-
Cyclohexene-3-yl] -azetidin-2-one A cyclohexene (21 ml) and dry diethyl ether (50 ml) were introduced into a 500 ml three-necked flask equipped with a thermometer and a partition. While stirring this solution-
After cooling to 5 °, borane dimethyl sulfide complex (2M tetrahydrofuran solution, 50 ml) was added slowly. The reaction mixture was stirred for 4 hours, then left for a further 2 hours and concentrated under reduced pressure. The white solid was suspended in dry tetrahydrofuran (80 ml) at room temperature under a nitrogen atmosphere, 1,3-cyclohexadiene (10 ml) was added, and the mixture was stirred for 18 hours. 4-Benzoyloxyazetidin-2-one (5.74 g) was added to this solution,
Cooled to 50 °. Diethyl zinc (1.1 M toluene solution, 30 ml) was added and stirred for 4 hours, and then warmed to room temperature. After an additional 1 hour, the reaction mixture was cooled to -70 °.
Cooled to and glacial acetic acid (10 ml) added. The reaction mixture was returned to room temperature and then stirred overnight. Ethyl acetate (3
(00 ml) was added, the organic phase was neutralized by washing with a saturated aqueous solution of sodium carbonate, dried over brine and anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue,
Flash chromatography on silica gel eluting with a mixture of 30% ethyl acetate and 70% cyclohexane to give the title compound as a colorless oil (4.53).
isolated as g).

Example 4 (4R) -1-t-butyldimethylsilyl-4-
[(3 ′S) -Cyclohexen-3-yl] -azetidi
N-2- one The compound of Example 1 (3.3 g) was dissolved in dry dimethylformamide (50 ml), and to this was added t-butyldimethylsilyl chloride (3.8 g) and triethylamine (4 ml) at room temperature under a nitrogen atmosphere. ) Was added. The reaction mixture was stirred for 2 hours, then diethyl ether (300 ml) was added. This solution was added to citric acid / sodium citrate pH = 3 buffer (2 × 200 ml), monopotassium phosphate / dipotassium phosphate pH = 7 buffer (100 ml),
And washed with brine (50 ml) then dried, filtered and the solvent removed under reduced pressure. The crude residue obtained was subjected to flash chromatography on silica gel eluting with a mixture of 10% ethyl acetate and 90% cyclohexane to isolate the title compound as a colorless oil (5.0 g).

IRVmax (cm ^-1 ): 1724 (C =
O-lactam) ¹ H-NMR (δ, ppm, CDCl ₃ ): 5.94-
5.87 (m, 1H), 5.74-5.67 (m, 1
H), 3.58 (m, 1H), 2.87 (dd, 1
H), 2.68 (dd, 1H), 2.55 (m, 1
H), 2.10-1.92 (m, 2H), 1.82-
1.74 (m), 1.62-1.48 (m), 1.14
-0.98 (m, 1H), 0.96 (s, 9H), 0.
28 (s, 3H), 0.20 (s, 1H)

Example 5 (3S, 4R) -1-t-butyldimethylsilyl-4-
[(3'S) -Cyclohexen-3-yl] -3-
[(1R) -1-t-butyldimethylsilyloxyethyl
] -Azetidin-2-one cooled (-78 °) diisopropylamine (0.
(38 ml) in dry tetrahydrofuran (10 ml) was added dropwise with n-butyllithium (2M hexane solution, 1.38 ml) under a nitrogen atmosphere to prepare a lithium diisopropylamide solution. The resulting solution was stirred at -78 ° for 30 minutes. A solution of the compound of Example 4 (660 mg) in dry tetrahydrofuran (15 ml) was added over 10 minutes and the mixture was stirred for additional 5 minutes, and then a solution of methyl t-butyldimethylsilylketone (0.44 g) in dry tetrahydrofuran (5 ml) was added. Was added. The reaction mixture was stirred at -78 ° for 10 minutes and then a solution of potassium t-butoxide (0.31 g) in t-butanol (1.8 ml) was added over 10 minutes. The reaction mixture was cooled to 0 over 10 minutes.
The mixture was warmed to 90 ° C., saturated aqueous ammonium chloride solution (4 ml) was added to quench the reaction, and the mixture was diluted with ethyl acetate (15 ml). The organic phase was washed with water (5 ml) and brine (5 ml) then dried, filtered and the solvent removed under reduced pressure. Xylene (20 ml) was added and it was removed under reduced pressure. The resulting residue was chromatographed on silica gel eluting with a mixture of 5% ethyl acetate in cyclohexane (Rf = 0.27) to isolate the title compound as a colorless solid (867mg).

M. p. 62.5-63.5 ° IRVmax (cm ⁻¹ ): 1732 (C═O) ¹ H-NMR (δ, ppm, CDCl ₃ ): 5.8
(M), 5.7 (m), 4.02 (m), 3.51
(T), 2.79 (dd), 2.5 (m), 2.00
(M), 1.8 (m), 1.2 (m), 1.22
(D), 0.96 (s), 0.88 (s), 0.26
(S), 0.20 (s), 0.07 (s), 0.06
(S)

Example 6 (3S, 4R) -4-[(3'S) -cyclohexene-
3-yl] -3-[(1R) -1-t-butyldimethyl
Silyloxyethyl] -azetidin-2-one A solution of the product of Example 5 (342 mg) in dry tetrahydrofuran (15 ml) was stirred while it was added to a solution of tetrabutylammonium fluoride (1.1 M containing glacial acetic acid (62 μl). Tetrahydrofuran solution, 0.92 ml) was added. After 10 minutes, the solution was treated with ethyl acetate (20 m
l) diluted with saturated aqueous sodium bicarbonate solution (5 ml)
Was added. After phase separation, the organic layer was washed with water (5 ml) and brine (5 ml), dried, filtered and the solvent removed under reduced pressure. The resulting residue was chromatographed on silica gel eluting with a mixture of 20% ethyl acetate in cyclohexane (Rf = 0.24) to isolate the title compound as a colorless solid (194mg).

IRVmax (cm ^-1 ): 3416 (N-
H), 1753 (C = O), 1603 (C = C) ¹ H-NMR (δ, ppm, CDCl ₃ ): 5.82
(M), 5.81 (m), 5.60 (dd), 4.14
(M), 3.46 (dd), 2.85 (m), 2.24
(M), 2.00 (m), 1.85-1.70 (m),
1.54 (m), 1.27 (m) aD = -42.4 (c = 1.14 in CHCl ₃ ).

Front page continuation (72) Inventor Stefano, Beyondi Italy Verona, Via, A, Fleming 2, Glaxo, Societa, Pell, Azioni (72) Inventor Tino, Rossi Italy Verona, Via, A, Fle Ming 2, 2, Glaxo, Societa, Pell, within Azioni (72) Inventor Stefania, Anna, Contini Italy Verona, Via, A, Fleming 2, Glaxo, Societa, Pell, within Azioni

Claims (9)

[Claims] 1. A compound of the general formula (I): (Here, R ₁ represents hydrogen or a nitrogen protecting group.) 2. A compound of the general formula (Ia). [Chemical 2] (Here, R ₁ has the meaning defined in claim 1.) 3. R ₁ is hydrogen, or tri (C _1-6 alkyl) silyl, C _1-4 alkylthio, C _1-6 alkoxymethyl, optionally substituted benzyloxymethyl and C _1- The compound according to claim 1 or 2, which represents a nitrogen protecting group selected from ₆ alkylsilyloxymethyl. 4. The compound according to any one of claims 1 to 3, wherein the nitrogen protecting group R ₁ is tri (C _1-6 alkyl) silyl. 5. (-) Erythro- (4R) -4 [(3 '
S) -Cyclohexen-3-yl] -azetidine-2-
on. 6. (4R) -1-t-Butyldimethylsilyl-4-[(3 ′S) -cyclohexen-3-yl] -azetidin-2-one. 7. A process for the preparation of a compound of formula (I) according to claim 1, comprising the azetidinone of formula (II): (Wherein R ₂ is C _1-4 alkyl, or optionally substituted phenyl), and a borane derivative (III): (Wherein each R ₃ represents a C _6-10 cycloalkyl group, or two R ₃ groups together represent 1,5-cyclooctadiyl) in the presence of a Lewis acid. , Then optionally or optionally, converting a compound of formula (I) wherein R ₁ is hydrogen to a compound of formula (I) wherein R ₁ is a nitrogen protecting group. 8. The method according to claim 7, wherein R ₃ represents a 2-methylcyclohexyl group or an isopinocanphenyl group. 9. The method according to claim 7, wherein the Lewis acid is titanium tetraisopropoxide or diethylzinc.